Serologically Documented Loracarbef (Lorabid)-InducedImmune Thrombocytopenia

O.S. Aljitawi,1 K. Krishnan,1* B.R. Curtis,2 D.W. Bougie,2 and R.H. Aster2

1Division of Hematology/Oncology and Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee StateUniversity, and James H. Quillen, VA Medical Center, Johnson City, Tennessee

2Blood Research Institute, Blood Center of Southeastern Wisconsin and Department of Medicine, Medical College of Wisconsin,Milwaukee, Wisconsin

We report here the first case of severe immune thrombocytopenia induced by a second-generation cephalosporin antibiotic, Loracarbef. A 56-year old white female developedacute severe thrombocytopenia associated with acute respiratory symptoms followingadministration of Loracarbef. She responded to Loracarbef withdrawal and systemiccorticosteroid administration. Loracarbef-dependent platelet-reactive antibodies weredemonstrable in her serum by flow cytometry. Am. J. Hematol. 73:41–43, 2003.© 2003 Wiley-Liss, Inc.

Key words: cephalosporins; loracarbef; immune thrombocytopenia

INTRODUCTION

Cephalosporin antibiotics are a recognized cause ofimmune hemolytic anemia [1–3]. However, patientstreated with this class of drugs can also experience life-threatening thrombocytopenia [1,4]. Cephalosporin-induced hemolytic anemia is associated with drug-dependent antibodies that act on red cells by severaldifferent mechanisms [1,5], but this has not been welldocumented for cephalosporin-induced thrombocytope-nia. We report here the first case of severe thrombocy-topenia associated with exposure to the second-genera-tion cephalosporin antibiotic loracarbef (Lorabid) andprovide evidence that a drug-dependent, platelet-reactiveantibody was the likely cause of platelet destruction.

CASE REPORT

A 56-year-old white female with a past medical his-tory of emphysema and hyperthyroidism was treated ather local hospital with a course of loracarbef, 200 mgdaily, for an upper respiratory tract infection. Severaldays later, her respiratory symptoms recurred and lora-carbef was reinstituted, this time at a dose of 400 mgdaily. After taking the first loracarbef tablet, she devel-oped acute breathlessness, wheezing, and tightness in thechest. She took diphenhydramine and was then broughtto the emergency room by ambulance; her BP was re-

corded as 126/71 mmHg. At the hospital, her conditionimproved after treatment with methylprednisolone andoxygen. Laboratory studies revealed normal electrolytesand coagulation indices. White count was 6,600/�L witha normal differential, hemoglobin was 12.6 g/dL, andplatelet count was 4,000/�L, confirmed by a manualcount. She denied illicit drug use and exposure to anymedication other than loracarbef. There was a past his-tory of penicillin sensitivity manifested by a skin rash.

The patient was transferred to a regional medical cen-ter for further diagnosis and treatment. Physical exami-nation on admission was essentially normal, except for awidespread petechial rash on the abdomen and both up-per extremities and bilateral wheezes in the chest. Therewas no other evidence of bleeding. Platelet count was14,000/�L. Intravenous methylprednisolone and oxygen

Contract grant sponsor: National Heart, Lung, and Blood Institute;Contract grant number: HL 13629

*Correspondence to: K. Krishnan, M.D., F.R.C.P., James H. QuillenCollege of Medicine, East Tennessee State University, Box 70622,Building 1, Dogwood Avenue, Johnson City, TN 37614

Received for publication 25 June 2002; Accepted 15 January 2003

Published online in Wiley InterScience (www.interscience.wiley.com).DOI: 10.1002/ajh.10307

American Journal of Hematology 73:41–43 (2003)

© 2003 Wiley-Liss, Inc.

were continued. On the next day, her platelet count was4,000/�L. Bone marrow examination revealed slight hy-pocellularity with normal hematopoiesis and adequatenumbers of megakaryocytes. Two days following admis-sion, platelets increased to 48,000/mL, and she was dis-charged on oral corticosteroids. Two days later, her plate-let count was 208,000/�L.

SEROLOGIC STUDIES

The patient’s serum was tested for loracarbef-dependent, platelet-reactive antibodies using flow cytom-etry to measure drug-dependent binding of antibody toplatelets [6]. In brief, 107 washed normal platelets wereincubated with loracarbef, 1 mg/mL, and 0.02 mL ofpatient serum in a total volume of 0.05 mL for 60 min.Controls consisted of the patient’s serum without drugand normal serum with and without drug. After incuba-tion at room temperature for 1 hr, the platelets werewashed three times in buffer containing drug at the sameconcentration as in the primary mixture. Platelet-boundantibody was then detected with fluorescein isothiocya-nate (FITC)-conjugated F(ab�)2 goat anti-human IgG Fcand IgM Fc antibodies (Jackson Immunoresearch Labo-ratory, Westgrove, PA) by flow cytometry (FACScan,Becton-Dickson, Mountain View, CA). A positive reac-tion is defined as a mean platelet fluorescence intensity(MFI) at least twice that of platelets processed identicallyexcept for the absence of drug. Reactions of this strengthalways exceed control values by at least three standarddeviations. In separate experiments, platelets pretreatedwith loracarbef at 1.0 mg/mL and then washed [1] werealso used as targets for antibody. Strong positive reac-tions (IgG only) were obtained when untreated plateletswere incubated with the patient’s serum and soluble lo-racarbef (Fig. 1). The patient’s serum gave much weakerreactions with normal platelets in the absence of the drug(Fig. 1). This was accounted for by antibodies specificfor class 1 HLA antigens, apparently stimulated by pre-vious pregnancies. No loracarbef-dependent antibodieswere detected in serum from 15 normal individuals.Negative reactions were also obtained when the patient’sserum was incubated with loracarbef-treated platelets inthe absence of soluble loracarbef. The loracarbef-dependent antibody was also detected in a serum sampleobtained 6 months after the thrombocytopenic episode.Detection of a loracarbef-dependent antibody in the pa-tient’s serum provides strong circumstantial evidencethat the thrombocytopenia was drug-induced. It seemslikely that the severe dyspnea experienced shortly aftertaking the loracarbef tablet, which appeared to have trig-gered the thrombocytopenia, was also related to drugsensitivity.

DISCUSSION

Although platelet destruction resulting from sensitivityto loracarbef has not been described previously, penicil-lin, penicillin derivatives, and other cephalosporin anti-biotics have been implicated as triggers for immunethrombocytopenia. The few cases of thrombocytopeniaassociated with penicillin treatment have been quite mild(platelets 35,000–75,000/mL) and have occurred in pa-tients given very high doses [7,8]. However, thrombocy-topenia induced by the penicillin derivatives methicillin[9], ampicillin [10], and piperacillin [11,12] can be verysevere and can be accompanied by bleeding symptoms.Although loracarbef-induced thrombocytopenia has notpreviously been reported, this side effect has been de-scribed in patients treated with other cephalosporins. The

Fig. 1. Fluorescence intensity on flow cytometry is de-picted in this illustration. A positive reaction is defined as amean platelet fluorescence intensity of at least twice that ofplatelets processed identically without the drug. Strongpositive reactions are seen when the patient’s serum istreated with loracarbef (curve D). (A) Normal serum withoutdrug; (B) normal serum plus loracarbef; (C) patient serumwithout drug; (D) patient serum plus loracarbef. Arbitraryfluorescence units are used on the abscissa.

42 Case Report: Aljitawi et al.

implicated drugs include first-generation [13,14], sec-ond-generation [15,16], and third-generation [17,18]cephalosporin compounds. In the reported cases, throm-bocytopenia generally occurred after 3–10 days of treat-ment, was usually severe (platelet counts less than10,000/�L), and was associated with significant bleedingsymptoms. After discontinuation of the implicated drug,platelet levels returned to normal within 3–10 days insurviving patients, but bleeding was fatal in one instance[17]. Immune hemolytic anemia, often life threateningand sometimes fatal, is also a recognized complication ofcephalosporin administration [1]. The mechanism bywhich cephalosporin antibiotics induce drug-dependent,cell-specific antibodies is unknown. By analogy with im-mune hemolytic anemia in patients receiving high-doseintravenous penicillin [1], it was suggested that cephalo-sporins, which also contain a �-lactam structure, linkspontaneously to membrane glycoproteins and act ashaptens to induce an immune response. If so, then re-exposure to the drug could create new targets for anti-body on cell membrane proteins, leading to blood celldestruction. However, antibodies reactive with drug-treated platelets could not be detected in patients withcephalosporin-induced thrombocytopenia [16,19] butwere identified when the drug was present in solubleform in the reaction mixture [4,16,19,20]. This was truein our patient as well (Fig. 1). How soluble drug pro-motes the tight binding of antibody to a cell membraneglycoprotein leading to platelet destruction is still unre-solved [21].

In summary, findings made in this case indicate thatloracarbef should be added to the list of cephalosporinantibiotics capable of causing acute immune thrombocy-topenia. When patients taking any medication developacute thrombocytopenia, it is important that a drug-induced etiology be considered, since failure to discon-tinue the sensitizing medication can have serious conse-quences. Fortunately, patients sensitive to one drugusually tolerate treatment with a different medication ofthe same class [21]. If an alternative cephalosporin com-pound is selected for a patient with cephalosporin-induced immune thrombocytopenia, however, it is wiseto choose one that has dissimilar side chains [4].

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Case Report: Loracarbef (Lorabid)-Induced Immune Thrombocytopenia 43